Orotracheal intubation is commonly performed in dogs undergoing general anesthesia. Although much work has been done on the cardiovascular effects of a variety of anesthetic induction agents,1–5 little is known about the cardiovascular effects of intubation in dogs. In humans, it is well documented that orotracheal intubation causes cardiovascular stimulation, most notably increases in HR and arterial blood pressure.6–8 These changes can be particularly concerning in patients with preexisting heart disease, systemic hypertension, and ocular or intracranial hypertension.9–13
Propofol and ketamine are IV administered anesthetic agents commonly used in dogs. Propofol abolishes laryngeal reflexes, leading to a smooth intubation.14,15 Conversely, intubation takes longer to achieve and the laryngeal gag reflex is less suppressed after ketamine administration.16 Cough has been associated with increases in arterial blood pressure and HR6,17 and is more likely to occur after administration of ketamine than after administration of propofol. Therefore, a greater increase in blood pressure in dogs intubated after the administration of ketamine is possible, compared with administration of propofol. In humans, intubation after induction with ketamine has been associated with similar cardiovascular stimulation seen after induction with thiopental18; however, intubation after induction with propofol is associated with less cardiac stimulation than with etomidate or thiopental.19 In dogs, however, 1 report6 indicates that laryngoscopy or tracheal intubation promotes vagal inhibition of the heart, leading to a decrease in HR and blood pressure. Since that report,6 only a few studies have evaluated the cardiovascular effects of intubation in dogs; either an increase in arterial blood pressure with no changes in HR following propofol or thiopental induction20–22 or no changes in either variable following propofol-atracurium induction have been found.23 However, the effect of intubation when different anesthetic agents are used is still poorly understood.
The objectives of the study reported here were to describe and compare the hemodynamic response to orotracheal intubation following induction of anesthesia with propofol, ketamine-propofol, and ketamine-diazepam in premedicated dogs. The hypotheses were that orotracheal intubation would lead to increased HR and arterial blood pressure and that greater increases would be observed in the dogs administered ketamine-diazepam, compared with dogs administered ketamine-propofol or propofol.
Materials and Methods
Animals—Ten healthy purpose-bred adult Beagles weighing (mean ± SD) 10.6 ± 1.4 kg (23.3 ± 3.1 lb) were included in the study. Dogs were considered healthy on the basis of results of physical examination, PCV, serum total protein concentration, serum BUN concentration, and serum glucose concentration. Dogs were individually housed, food was withheld for 12 hours prior to the study, and dogs had access to water ad libitum. An institutional animal care and use committee approved this study.
Instrumentation—On the day of the study, anesthesia was induced and maintained with isoflurane in 100% oxygen delivered via face mask. The vaporizer was adjusted to maintain a light plane of anesthesia as assessed by eye position, reflexes, and masseter muscle (jaw) tone. All dogs were positioned in lateral recumbency, and a 20-gauge, 1.5-inch IV catheter was aseptically placed in the cephalic vein and used for drug administration. A 22-gauge, 1.5-inch arterial catheter was aseptically placed in the dorsal pedal artery and used for direct measurement of SAP, MAP, and DAP and to allow lithium dilution measurement of CO. The lateral aspects of both hemithoraxes were clipped of hair, and conductive padsa (1 on the right and 2 on the left) were applied to the skin to monitor a lead II ECG throughout the experimental period. After instrumentation, dogs were allowed to recover completely from anesthesia until they were able to stand and walk without assistance or ataxia.
Experimental design and procedures—A minimum of 40 minutes after discontinuation of isoflurane administration was allowed before determination of complete anesthetic recovery. Dogs were kept in a sitting position or in lateral recumbency with minimal restraint during the calibration period. The dorsal pedal artery catheter was connected to a calibrated disposable transducer zeroed at the level of the sternum. A single CO determination was performed and used to calibrate the monitorb for continuous observation of CO and SV. Acepromazinec (0.02 mg/kg [0.009 mg/lb]) and oxymorphoned (0.05 mg/kg [0.023 mg/lb]) were administered IV for sedation (premedication). Fifteen minutes after premedication, anesthesia was induced. Three anesthetic protocols were used and assigned randomly by use of a balanced incomplete block design such that each dog was sequentially anesthetized by use of 2 of the 3 protocols, with a 1-week washout period between protocols. The protocols consisted of propofole administered at 4 mg/kg (1.8 mg/lb) to 6 dogs, a 1:1 mixture of propofol administered at 2 mg/kg (0.9 mg/lb) plus ketamine hydrochloridef administered at 2 mg/kg (mixed in the same syringe) to 7 dogs, or ketamine hydrochloride administered at 5 mg/kg (2.3 mg/lb) plus diazepamg administered at 0.2 mg/kg (0.09 mg/lb; mixed in the same syringe) to 6 dogs. The drug doses were selected on the basis of results of a previous study24 and the authors' clinical experience. The anesthetic agents were administered IV by hand over 60 seconds, after which the dogs were left undisturbed. Data collection started 5 minutes after administration of the anesthetic agent to avoid interfering with an unrelated study being conducted with the same dogs. The person collecting the data was unaware of which anesthetic agents were administered. Dogs were then positioned in sternal recumbency, and intubation was performed without the use of a laryngoscope. The trachea was intubated by use of a highvolume, low-pressure, cuffed Murphy-type polyvinyl chloride orotracheal tubeh with an internal diameter of 7 mm (1 dog), 7.5 mm (5 dogs), or 8 mm (4 dogs). The same orotracheal tube size was used for both anesthetic events for each dog. The same experienced anesthetist performed the orotracheal intubation in all dogs.
Data collection—Data were collected 5 minutes after induction of anesthesia and immediately before intubation (baseline), at intubation (T0), and 30, 60, 90, 120, 150, and 180 seconds after intubation (T30, T60, T90, T120, T150 and T180, respectively; Figure 1). The baseline value was considered the mean value derived from measurements obtained from minus 120 seconds to intubation, the T0 (intubation) value was considered the mean value derived from measurements obtained from 5 seconds before intubation until 5 seconds after intubation, the T30 value was considered the mean value derived from measurements obtained from intubation to 30 seconds thereafter, the T60 value was considered the mean value derived from measurements obtained from 30 to 60 seconds following intubation, and the remaining values were determined in the same manner. Plasma sodium and hemoglobin concentrations were measured before premedication and used as required for the lithium dilution CO monitor.i The initial determination of CO was performed before premedication to calibrate the monitor. A bolus injection of lithium chloridej (1 mL; 0.15 mmol) followed by 2 mL of saline (0.9% NaCl) solution was given IV over 10 seconds through the cephalic catheter. Subsequent determinations of CO were obtained by use of the pulse contour technology from the monitor.b Mean measurements for CO, SV, SVR, HR, SAP, MAP, and DAP recorded from the monitor were determined over a specific period to obtain a final value for each time point. Cardiac output and SV were indexed by use of surface area. After intubation, the dogs were administered isoflurane for participation in a different study. Dogs were allowed to recover from anesthesia after all experimental procedures were concluded.
Experimental design of a study of the cardiovascular effects of orotracheal intubation following anesthetic induction with propofol, ketamine-propofol, or ketamine-diazepam in premedicated dogs.
Citation: Journal of the American Veterinary Medical Association 244, 8; 10.2460/javma.244.8.934
Statistical analysis—All analyses were selected and performed by a biostatistician in consultation with the authors. Normal probability plots revealed that all data followed a normal distribution. Subsequently, these outcomes were summarized as mean ± SD values. The association between time periods and outcomes was assessed with a mixed-model ANOVA. The linear model specified time, protocol (propofol vs ketamine-propofol vs ketamine-diazepam), and time × protocol as fixed effects; the Kenward-Roger approximation was used for calculation of the degrees of freedom. Dog identification was specified as the random effect. To specifically assess the effect of time period within each protocol, the time × protocol interaction was examined by use of a software procedure.k Effect of protocol on outcomes was assessed by use of mixed-model ANCOVA. The linear model specified baseline measurement, time, protocol, and time × protocol as fixed effects; the Kenward-Roger approximation was used for calculation of the degrees of freedom. Dog identification was specified as the random effect. To specifically assess the effect of protocol at each time period, the time × protocol interaction was examined by use of the slice and slicediff options of the software procedure.k For each model, slice-level P values were adjusted for multiple comparisons (across all outcomes) by use of the Benjamini-Hochberg false discovery rate method. For each outcome with a significant slice-level P value (after the Benjamini-Hochberg adjustment), 2-way comparisons (slicediff-level P values) were adjusted for multiple comparisons by use of the Tukey procedure. For each outcome, residual plots were inspected to verify model adequacy (ie, the errors were normally distributed with a constant variance). For all comparisons, P < 0.05 was considered significant. All analyses were performed with computer software.l
Results
Orotracheal intubation was possible with the stipulated doses on 16 occasions and not possible on 3 occasions (2 in the ketamine-propofol group and 1 in the ketamine-diazepam group, for which these data were removed from the analyses). Four dogs in the ketamine-diazepam group and 1 in the propofol group had a slight cough after intubation, although placement of the tube was unremarkable. In 1 dog, a different orotracheal tube size was used for the second anesthetic event (ketamine-propofol group, 7 mm; ketamine-diazepam group, 7.5 mm). The isoflurane vaporizer was turned on at a median of 97 seconds (range, 35 to 317 seconds) after intubation.
Differences over time were observed for SAP, MAP, and DAP. In the ketamine-diazepam group, a significant (P = 0.028) increase in SAP was detected at T30, compared with baseline, with a steady decline observed over time (T90, T120, T150, and T180 values were significantly lower than T0 and T30 values), until values returned to baseline. For MAP, values at T90, T120, T150, and T180 were also significantly lower than values at T30, although none of the values were different from baseline. For DAP, the T120 value was significantly lower than the T0 (P = 0.046) and T30 values (P = 0.031).
In the ketamine-propofol group, SAP was significantly lower at T180, compared with baseline, T0, and T30. For MAP, the T180 value was significantly lower than the T0 and T30 values. No differences for DAP were detected.
In the propofol group, significantly lower values for SAP were detected at T180, compared with T0, T30, and T90. No differences were observed for MAP or DAP. No additional differences were observed among groups for the other variables at any time points (Table 1).
Mean ± SD values for cardiovascular variables measured in premedicated dogs 5 minutes after induction of anesthesia and immediately before intubation (baseline), at orotracheal intubation (T0), and 30 (T30), 60 (T60), 90 (T90), 120 (T120), 150 (T150), and 180 (T180) seconds after intubation.
| Variable | Induction agent | Baseline | T0 | T30 | T60 | T90 | T120 | T150 | T180 |
|---|---|---|---|---|---|---|---|---|---|
| HR (beats/min) | Propofol | 94 ± 9 | 108 ± 13 | 101 ± 11 | 95 ± 19 | 90 ± 15 | 92 ± 12 | 92 ± 13 | 90 ± 12 |
| Ketamine-propofol | 100 ± 24 | 110 ± 41 | 107 ± 27 | 104 ± 22 | 92 ± 22 | 93 ± 17 | 99 ± 12 | 97 ± 8 | |
| Ketamine-diazepam | 140 ± 42 | 149 ± 48 | 143 ± 48 | 150 ± 64 | 170 ± 27 | 149 ± 60 | 143 ± 60 | 136 ± 61 | |
| CI (L/min/m2) | Propofol | 3.9 ± 1.1 | 4.2 ± 1.0 | 4.3 ± 1.1 | 3.5 ± 2.0 | 2.8 ± 1.7 | 3.8 ± 1.0 | 3.8 ± 1.1 | 3.6 ± 0.9 |
| Ketamine-propofol | 4.9 ± 1.5 | 4.7 ± 1.9 | 4.6 ± 1.6 | 5.2 ± 1.8 | 3.7 ± 2.3 | 3.7 ± 2.2 | 2.6 ± 2.4 | 3.2 ± 1.9 | |
| Ketamine-diazepam | 7.1 ± 3.2 | 7.5 ± 4.0 | 7.0 ± 2.9 | 8.1 ± 3.5 | 7.6 ± 4.5 | 7.6 ± 3.0 | 6.9 ± 2.7 | 6.5 ± 2.6 | |
| SI (mL/beat/m2) | Propofol | 41 ± 11 | 40 ± 9 | 41 ± 11 | 36 ± 21 | 30 ± 17 | 40 ± 10 | 41 ± 11 | 40 ± 11 |
| Ketamine-propofol | 50 ± 10 | 44 ± 12 | 44 ± 14 | 50 ± 15 | 50 ± 11 | 49 ± 12 | 32 ± 21 | 33 ± 19 | |
| Ketamine-diazepam | 50 ± 18 | 49 ± 15 | 49 ± 13 | 54 ± 15 | 46 ± 27 | 52 ± 17 | 49 ± 17 | 49 ± 17 | |
| SAP (mm Hg) | Propofol | 130 ± 9 | 135 ± 8 | 140 ± 15 | 131 ± 7 | 138 ± 12 | 128 ± 15 | 124 ± 11 | 119 ± 11 |
| Ketamine-propofol | 136 ± 15 | 143 ± 8 | 145 ± 12 | 142 ± 12 | 131 ± 15 | 137 ± 7 | 130 ± 4 | 118 ± 18 | |
| Ketamine-diazepam | 145 ± 14 | 158 ± 13 | 164 ± 16 | 146 ± 16 | 135 ± 15 | 133 ± 15 | 131 ± 15 | 132 ± 13 | |
| MAP (mm Hg) | Propofol | 69 ± 8 | 77 ± 9 | 78 ± 11 | 72 ± 8 | 76 ± 8 | 71 ± 15 | 66 ± 8 | 63 ± 8 |
| Ketamine-propofol | 76 ± 2 | 86 ± 17 | 88 ± 20 | 83 ± 15 | 73 ± 9 | 75 ± 2 | 71 ± 4 | 68 ± 5 | |
| Ketamine-diazepam | 91 ± 7 | 99 ± 13 | 103 ± 15 | 90 ± 15 | 88 ± 11 | 84 ± 8 | 84 ± 7 | 83 ± 4 | |
| DAP (mm Hg) | Propofol | 50 ± 7 | 58 ± 9 | 56 ± 11 | 51 ± 9 | 55 ± 7 | 49 ± 10 | 46 ± 8 | 46 ± 8 |
| Ketamine-propofol | 55 ± 5 | 67 ± 19 | 68 ± 20 | 57 ± 15 | 53 ± 7 | 54 ± 2 | 52 ± 4 | 50 ± 5 | |
| Ketamine-diazepam | 71 ± 9 | 80 ± 15 | 81 ± 17 | 65 ± 14 | 68 ± 12 | 63 ± 9 | 64 ± 7 | 66 ± 5 | |
| SVR | Propofol | 2,882 ± 783 | 2,906 ± 735 | 3,215 ± 909 | 2,942 ± 992 | 3,726 ± 770 | 3,141 ± 974 | 2,834 ± 856 | 2,636 ± 827 |
| (dynes/cm5) | Ketamine-propofol | 2,677 ± 755 | 3,232 ± 1,174 | 3,462 ± 1,697 | 2,937 ± 1,106 | 2,649 ± 727 | 2,715 ± 608 | 2,643 ± 206 | 2,598 ± 340 |
| Ketamine-diazepam | 2,547 ± 1,224 | 2,673 ± 1,001 | 2,895 ± 1,019 | 2,400 ± 1,337 | 1,614 ± 322 | 2,221 ± 1,350 | 2,453 ± 1,678 | 2,740 ± 2,190 |
Anesthetic induction was performed with propofol (4 mg/kg [1.8 mg/lb]) in 6 dogs, ketamine hydrochloride (2 mg/kg [0.9 mg/lb]) and propofol (2 mg/kg) in 7 dogs, and ketamine hydrochloride (5 mg/kg [2.3 mg/lb]) and diazepam (0.2 mg/kg [0.09 mg/lb]) in 6 dogs; anesthetics were administered IV after premedication with acepromazine (0.02 mg/kg [0.009 mg/lb]) and oxymorphone (0.05 mg/kg [0.023 mg/lb]), IV.
CI = Cardiac output indexed to body surface area. SI = Stroke volume indexed to body surface area.
Discussion
In this study, data collection occurred within the first 180 seconds after intubation. Katz et al18 determined that blood pressure and HR increase within 30 seconds after orotracheal tube placement in humans, with further increases observed by 60 seconds. Therefore, any hemodynamic changes resulting from the orotracheal intubation would have been observed during the period studied. In the present study, administration of isoflurane began a median of 97 seconds after intubation, and it is possible that a relevant inspired concentration of isoflurane was achieved by 180 seconds. This could explain the observed gradual decrease in blood pressure over time because isoflurane is a known hypotensive agent. However, this should not have affected the early changes that were detected in some variables in the ketamine-diazepam group. In that group, at the 30-second time point, a significant increase from baseline was observed in SAP, consistent with a previous study25 in humans that used ketamine for induction of anesthesia. Gold et al25 determined that profound cardiovascular stimulation following intubation is observed in humans after anesthetic induction with ketamine. However, this effect was not observed in the ketamine-propofol group studied here, which indicated that propofol blunted the response to intubation when administered with ketamine.
Interestingly, Hofmeister et al22 observed a significant increase in arterial blood pressure following intubation when lower doses of propofol (4.0 to 5.6 mg/kg [1.8 to 2.5 mg/lb]) were used for anesthetic induction. However, when higher doses of propofol (6.6 to 8.3 mg/kg [3.0 to 3.8 mg/lb]) were administered prior to intubation, no significant increase in HR and blood pressure occurred. In the present study, intubation was performed 5 minutes after induction of anesthesia. At this time, the drugs administered at induction had taken full effect, in contrast to when intubation is performed immediately after drug administration. It is possible that the dose of propofol administered in the present study (4.0 mg/kg) could have resulted in a cardiovascular response to intubation similar to the high doses (6.6 to 8.3 mg/kg) studied by Hofmeister et al,22 suggesting that when the depth of anesthesia is adequate, propofol given prior to intubation may prevent tachycardia and hypertension in dogs. Our results for the ketamine-propofol group (ie, no significant increase in any variables after intubation) were similar to those of Furuya et al.26 In that study, ketamine administered 1 minute prior to propofol induction prevented postinduction hypotension from propofol and postintubation hypertension from ketamine.25
In the study reported here, dogs were premedicated with acepromazine and oxymorphone, which is a common combination used in clinical practice. The mechanism by which intubation in humans causes cardiovascular stimulation is thought to be sympathetic stimulation and a consequent catecholamine discharge.27 Although chronic use of phenothiazines decreased the blood pressure response to catecholamines in 1 study, the use of a single dose (such as for premedication) did not.28 Therefore, administration of acepromazine in the present study may have reduced this response, although not completely. Conversely, oxymorphone is an opioid analgesic for which the main cardiovascular effect is a mild decrease in HR.29,30 As for most opioids, oxymorphone is also an antitussive agent. As such, it could have suppressed the cough reflex and therefore indirectly suppressed the cardiovascular response to intubation because coughing increases blood pressure and HR.17 Kojima et al31 observed that the combination of acepromazine and butorphanol followed by either propofol or thiopental induced less tachycardia after intubation in dogs than was observed in a group that received saline solution as a placebo for premedication. Conversely, Hofmeister et al23 observed no increase in HR or arterial blood pressure after intubation in unpremedicated dogs in which anesthesia was induced with propofol-atracurium. Although the premedication used in the present study could have influenced the results, we chose to study the effects of the induction drugs in premedicated dogs because of the direct clinical applicability of the results.
In this study, a laryngoscope was not used to aid intubation to avoid any possible confounding stimulation from laryngoscopy. In humans, laryngoscopy alone is enough to cause an increase in arterial blood pressure, compared with preinduction values,32 and arterial blood pressure further increases after orotracheal intubation. In dogs, the cardiovascular effects of laryngoscopy are poorly described and conflicting in the literature. King et al6 observed that laryngoscopy alone caused a decrease in blood pressure and pulse rate, an effect that was further enhanced by orotracheal intubation. Conversely, Jolliffe et al20 and Hofmeister et al.21,22 observed an increase in arterial blood pressure after laryngoscopy and intubation, but the separate effect of each intervention cannot be distinguished in their work. No other studies of the cardiovascular effects of laryngoscopy in dogs have been performed to our knowledge.
The size of the orotracheal tube could be an important factor in the cardiovascular response to intubation. A tight-fitting orotracheal tube may result in greater airway stimulation, leading to a greater cardiovascular response, whereas a loose-fitting tube may not elicit any response. With the exception of 1 dog, the same orotracheal tube size was used for the 2 anesthetic events; therefore, any differences among groups were most likely related to the induction drug protocol than to different magnitudes of stimulation of the airway during intubation. The orotracheal tube sizes used here were selected by an experienced anesthetist after digital palpation of the external diameter of the trachea and visual identification of the glottis. Therefore, it is unlikely that a direct effect from the orotracheal tubes used was present.
The present study had no control group in which data would have been collected at the same time points with no orotracheal intubation. Although possible, it is unlikely that the changes observed over time were a result of the sole effect of the anesthetic drugs and not of the orotracheal intubation. The data were collected 5 minutes after the induction agents were administered. At this point, the hemodynamic effects of the drugs were well established. When groups were compared by use of the baseline value for each variable as a covariate, no differences were detected between baseline values and T0 values. All dogs were handled in the same manner. Therefore, the observed changes can be attributed most likely to orotracheal intubation.
The method chosen for CO monitoring was pulse contour analysis with calibration by means of lithium dilution. The recommended route for lithium administration is a central line, but we administered lithium via the cephalic vein. According to Mason et al,33 the cephalic vein is also a suitable route because the CO values are similar to those obtained by use of the jugular vein. Different than more traditional clinical CO methods (thermodilution and lithium dilution), the pulse contour technology allows for beat-by-beat assessment. This was essential for our study because time points were just 30 seconds apart and the use of other methods would not have been feasible. The pulse contour method analyzes the arterial waveform, and changes in vascular tone could interfere with its measurement. The intubation-related cardiovascular response results from the release of cathecholamines,27 so changes in vascular tone could have occurred. In the ketamine-diazepam group, the increase in blood pressure was not accompanied by an increase in HR. Because there was no substantial change in blood volume, a change in vascular tone may have occurred. However, SVR measured by the pulse contour method was not significantly different in this group. It is possible that the monitor did not detect this change or that clinically important changes did not occur. Alternative technologies for beat-by-beat CO monitoring include continuous thermodilution, transesophageal and transthoracic Doppler echocardiography, and transthoracic electrical bioimpedance.34
In the present study, 4 dogs in the ketamine-diazepam group and 1 in the propofol group had a mild cough after intubation. Cough has been associated with increased arterial blood pressure and HR6,17 and may have affected hemodynamic variables recorded early in the study, although the cough observed was mild and resolved without treatment. A significant increase in blood pressure was detected at the 30-second time point in the ketamine-diazepam group, although no changes in HR or any other cardiovascular variables were observed.
Orotracheal intubation without the use of a laryngoscope following anesthetic induction with ketamine-diazepam induced mild and transitory hypertension in the healthy premedicated dogs in the present study. Intubation did not result in cardiovascular stimulation after induction with propofol or ketamine-propofol. In dogs with preexisting hypertension or when an increase in blood pressure may not be well tolerated, propofol or propofol-ketamine appears to be better alternatives for induction of anesthesia and orotracheal intubation, compared with ketamine-diazepam.
ABBREVIATION
| CO | Cardiac output |
| DAP | Diastolic arterial blood pressure |
| HR | Heart rate |
| MAP | Mean arterial blood pressure |
| SAP | Systolic arterial blood pressure |
| SV | Stroke volume |
| SVR | Systemic vascular resistance |
Conmed Healthcare Management Inc, Hanover, Md.
LidCOplus, LidCO Ltd, London, England.
Acepromazine maleate injection (1 mg/mL), Phoenix Scientific Inc, St Joseph, Mo.
Numorphan, Endo Pharmaceuticals Inc, Chadds Ford, Pa.
PropoFlo (10 mg/mL), Abbott Laboratories, North Chicago, Ill.
Ketaset (100 mg/mL), Fort Dodge Animal Health, Fort Dodge, Iowa.
Diazepam (5 mg/mL), Abbott Laboratories, North Chicago, Ill.
Sheridan, Teleflex Medical, Research Triangle Park, NC.
I-STAT, Abbott Point of Care Inc, East Windsor, NJ.
Lithium chloride, LiDCO Ltd, London, England.
GLIMMIX, SAS, SAS Institute Inc, Cary, NC.
SAS, version 9.3, SAS Institute Inc, Cary, NC.
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